Background: End-stage liver disease secondary to hepatitis C virus (HCV) infection is the leading indication for orthotopic liver transplantation (OLT) in the United States. Recurrence of HCV infection is nearly universal, with 10 of HCV-infected recipients experiencing early graft loss or death secondary to recurrent HCV disease. The National Institutes of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database (LTD) has recently demonstrated that the pre- OLT viral load, as measured by HCV RNA, is predictive of patient and graft survival. It is not known whether lowering pre-OLT viral load will improve the rate of virological recurrence, or patient or graft survival following OLT in HCV-infected recipients. Aims: A planning grant is proposed for the design of a multi-center, double-blind, randomized, controlled trial incorporating interferon- alpha (IFN-alpha) and ribavirin to be conducted by the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database in conjunction with three additional Liver Transplant Centers. In order to design such a study, the specific aims of the planning grant proposal are: 1) to establish optimal study size and duration (power calculations, stratification strategy) through the virological characterization of the HCV-infected patients currently awaiting liver transplantation at the participating centers and 2) to determine the tolerability and efficacy of two forms of IFN-alpha and ribavirin in patients with end-stage liver disease secondary to HCV. Methods: HCV-infected patients awaiting OLT at the participating centers (the Mayo Clinic and Foundation, Mount Sinai Medical Center, New York, the University of California San Francisco, the University of Pittsburgh, the University of Nebraska and Baylor University Medical Center) will be invited to participate in the study. Sixty participants will be randomized to receive either non-pegylated IFN-alpha alone, non- pegylated IFN-alpha + ribavirin or pegylated IFN-alpha + ribavirin. Statistical analysis will be performed by the Graduate School of Public Health at the University of Pittsburgh. Significance: The results of the planning phase will facilitate the design and coordination of the multi-center double-blind, randomized, controlled trial incorporating IFN-alpha and ribavirin to determine the effect of lowering pre-OLT HCV RNA titers on posttransplant outcomes, including HCV recurrence.